Analysis of compensatory β-cell response in mice with combined mutations of Insr and Irs2

Jane J. Kim, Yoshiaki Kido, Philipp E. Scherer, Morris F. White, Domenico Accili

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

Type 2 diabetes results from impaired insulin action and β-cell dysfunction. There are at least two components to β-cell dysfunction: impaired insulin secretion and decreased β-cell mass. To analyze how these two variables contribute to the progressive deterioration of metabolic control seen in diabetes, we asked whether mice with impaired β-cell growth due to Irs2 ablation would be able to mount a compensatory response in the background of insulin resistance caused by Insr haploinsufficiency. As previously reported, ∼70% of mice with combined Insr and Irs2 mutations developed diabetes as a consequence of markedly decreased β-cell mass. In the initial phases of the disease, we observed a robust increase in circulating insulin levels, even as β-cell mass gradually declined, indicating that replication-defective β-cells compensate for insulin resistance by increasing insulin secretion. These data provide further evidence for a heterogeneous β-cell response to insulin resistance, in which compensation can be temporarily achieved by increasing function when mass is limited. The eventual failure of compensatory insulin secretion suggests that a comprehensive treatment of β-cell dysfunction in type 2 diabetes should positively affect both aspects of β-cell physiology.

Original languageEnglish (US)
Pages (from-to)E1694-E1701
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume292
Issue number6
DOIs
StatePublished - Jun 1 2007

Keywords

  • Genetics
  • Insulin receptor
  • Insulin receptor substrate-2
  • Insulin resistance
  • Insulin signaling
  • Knockout mice
  • β-cell compensation

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Physiology (medical)

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